MAPK/ERK kinase (MEK1/2) is an integral component of the RAF/MEK/ERK signaling pathway implicated in uncontrolled cell proliferation and cell survival. AZD6244 (ARRY-142886), a novel, selective, ATP uncompetitive inhibitor of MEK 1/2 is currently in phase II monotherapy clinical trials in a range of diseases. In order to evaluate the potential of AZD6244 to combine with the agents currently used to treat these cancers we have used in vivo human tumor xenograft models. The agents used included drugs with a cytotoxic mechanism for example, irinotecan, docetaxel, gemcitabine and also those with a targeted mechanism, for example, gefitinib. Since the predominant effect of MEK inhibition is inhibition of cell proliferation by arresting tumor cells in phases G0/G1 of the cell cycle we investigated the impact of altering the sequence of administration with drugs that may require cells to be in a different phase of the cell cycle. The combination of AZD6244 and gefitinib was found to offer a significant improvement in tumor growth inhibition in a colorectal cancer xenograft, LoVo which carries a KRAS gene mutation. Acute dosing studies with pharmacodynamic assessments were utilized to investigate the mechanisms of the beneficial effects of the combination of AZD6244 with docetaxel and gefitinib.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA